Sestrin2 regulates monocyte activation through AMPK‐mTOR nexus under high‐glucose and dyslipidemic conditions

Abstract

The vicious cycle between hyperinsulinemia and insulin resistance results in the progression of atherosclerosis in the vessel wall. The complex interaction between hyperglycemia and lipoprotein abnormalities promotes the development of atherogenesis. In the early phase of atherosclerosis, macrophage‐derived foam cells play an important role in vascular remodeling. Mechanistic target of rapamycin (mTOR) signaling pathway has been identified to play an essential role in the initiation, progression, and complication of atherosclerosis. Recently sestrin2, an antioxidant, was shown to modulate TOR activity and thereby regulating glucose and lipid metabolism. But the role of sestrin2 in monocyte activation is still not clearly understood. Hence, this study is focussed on investigating the role of sestrin2 in monocyte activation under hyperglycemic and dyslipidemic conditions. High‐glucose and oxidized low‐density lipoprotein (LDL) treatments mediated proinflammatory cytokine production (M1) with a concomitant decrease in the anti‐inflammatory cytokine (M2) levels in human monocytic THP1 cells. Both glucose and oxidized LDL (OxLDL) in a dose and time‐dependent manner increased the mTOR activation with a marked reduction in the levels of pAMPK and sestrin2 expression. Both high‐glucose and OxLDL treatment increased foam cell formation and adhesion of THP1 cells to endothelial cells. Experiments employing activator or inhibitor of adenosine monophosphate kinase (AMPK) as well as overexpression or silencing of sestrin2 indicated that high‐glucose mediated monocyte polarization and adhesion of monocytes to the endothelial cells were appeared to be programmed via sestrin2‐AMPK‐mTOR nexus. Our results evidently suggest that sestrin2 plays a major role in regulating monocyte activation via the AMPK–mTOR‐pathway under diabetic and dyslipidemic conditions and also AMPK regulates sestrin2 in a feedback mechanism.

Physical fitness status modulates the inflammatory proteins in peripheral blood and circulating monocytes: role of PPAR-gamma

“…In this perspective, two molecular pathways are related with anti-inflammatory response together with the metabolic reprogramming in myeloid cells. On the one hand AMP-activated protein kinase (AMPK), a kinase energetic sensor, induces the oxidative pathway in immune cells, promoting an anti-inflammatory profile in macrophages and lymphocytes, chronically 23 .…”

Sestrin2: Its Potential Role and Regulatory Mechanism in Host Immune Response in Diseases

“…Moreover, SESN2-knockdown mice had higher plasma pro-inflammatory cytokine levels and increased monocyte recruitment to the vascular endothelium by secreting monocyte adhesion molecules [intercellular adhesion molecule (ICAM)-1 and vascular cell adhesion molecule (VCAM)-1] through inhibiting the AMPK signaling pathway and downregulating the ER stress pathway, which contributed to atherosclerosis initiation (32). Similarly, another study reported that SESN2 regulated monocyte polarization and adhesion to endothelial cells and decreased inflammatory responses by regulating the AMPK–mTOR nexus under high-glucose and dyslipidemic conditions (95). Moreover, in a sepsis mouse model and in septic shock patients, SESN2 levels were increased and peaked at 48 h in blood monocytes, and SESN2 protected organisms against inflammatory responses and septic shock, which were associated with decreased serum concentrations of IL-1β and IL-18 (12).…”

The Protective Role of Sestrin2 in Atherosclerotic and Cardiac Diseases

“…The AMPK and mTOR signaling pathways were reported to play an essential role in the initiation and progression of atherosclerosis [ 29 , 30 ], and sestrin2 was shown to modulate mTOR activity, thereby regulating glucose and lipid metabolism [ 31 , 32 ]. Sundararajan et al reported that high-glucose and oxidized LDL treatment mediated the production of proinflammatory cytokine (M1) with a concomitant decrease in anti-inflammatory cytokine (M2) levels in macrophages [ 33 ]. M2 macrophages promote the secretion of IL-10, transforming growth factor-β (TGF-β), and extracellular matrix to protect vessels from atherosclerosis, whereas M1 macrophages secrete matrix metalloproteinases (MMPs) and proinflammatory factors such as TNF-α, IL-6, and IL-1β [ 34 ].…”

“…M2 macrophages promote the secretion of IL-10, transforming growth factor-β (TGF-β), and extracellular matrix to protect vessels from atherosclerosis, whereas M1 macrophages secrete matrix metalloproteinases (MMPs) and proinflammatory factors such as TNF-α, IL-6, and IL-1β [ 34 ]. Glucose and oxidized LDL increased mTOR activation with a marked reduction in AMPK and sestrin2 expression and increased foam cell formation and monocyte adhesion to endothelial cells [ 33 ]. In addition, the overexpression of sestrin2 regulated the polarization of macrophages toward anti-inflammatory M2, while the knockdown of sestrin2 directed the polarization toward proinflammatory M1 [ 33 ].…”

“…Glucose and oxidized LDL increased mTOR activation with a marked reduction in AMPK and sestrin2 expression and increased foam cell formation and monocyte adhesion to endothelial cells [ 33 ]. In addition, the overexpression of sestrin2 regulated the polarization of macrophages toward anti-inflammatory M2, while the knockdown of sestrin2 directed the polarization toward proinflammatory M1 [ 33 ]. These findings suggested that sestrin2 plays a major role in regulating monocyte activation via the AMPK-mTOR signaling pathway under diabetic and dyslipidemic conditions and that sestrin2 has a protective role against atherosclerosis.…”